JPH08510255A - 接合−安定化ポリペプチド組成物 - Google Patents

接合−安定化ポリペプチド組成物

Info

Publication number
JPH08510255A
JPH08510255A JP6525657A JP52565794A JPH08510255A JP H08510255 A JPH08510255 A JP H08510255A JP 6525657 A JP6525657 A JP 6525657A JP 52565794 A JP52565794 A JP 52565794A JP H08510255 A JPH08510255 A JP H08510255A
Authority
JP
Japan
Prior art keywords
peptide
polymer
insulin
group
moiety
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
JP6525657A
Other languages
English (en)
Japanese (ja)
Inventor
エクウライブ.ノッチリ.ヌケム
Original Assignee
プロティン.デリバリー.インコーポレイテッド
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by プロティン.デリバリー.インコーポレイテッド filed Critical プロティン.デリバリー.インコーポレイテッド
Publication of JPH08510255A publication Critical patent/JPH08510255A/ja
Withdrawn legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/96Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/48Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575Hormones
    • C07K14/62Insulins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Wood Science & Technology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • General Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
JP6525657A 1993-05-10 1994-05-10 接合−安定化ポリペプチド組成物 Withdrawn JPH08510255A (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/059,701 US5359030A (en) 1993-05-10 1993-05-10 Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same
US08/059,701 1993-05-10
PCT/US1994/005204 WO1994026778A1 (en) 1993-05-10 1994-05-10 Conjugation-stabilized polypeptide compositions

Related Child Applications (2)

Application Number Title Priority Date Filing Date
JP2002260459A Division JP2003160598A (ja) 1993-05-10 2002-09-05 接合安定化されたポリペプチド組成物
JP2002260460A Division JP4482267B2 (ja) 1993-05-10 2002-09-05 接合安定化されたポリペプチド組成物

Publications (1)

Publication Number Publication Date
JPH08510255A true JPH08510255A (ja) 1996-10-29

Family

ID=22024685

Family Applications (4)

Application Number Title Priority Date Filing Date
JP6525657A Withdrawn JPH08510255A (ja) 1993-05-10 1994-05-10 接合−安定化ポリペプチド組成物
JP2002260460A Expired - Lifetime JP4482267B2 (ja) 1993-05-10 2002-09-05 接合安定化されたポリペプチド組成物
JP2002260459A Pending JP2003160598A (ja) 1993-05-10 2002-09-05 接合安定化されたポリペプチド組成物
JP2006202440A Expired - Lifetime JP4012928B2 (ja) 1993-05-10 2006-07-25 接合安定化されたポリペプチド組成物

Family Applications After (3)

Application Number Title Priority Date Filing Date
JP2002260460A Expired - Lifetime JP4482267B2 (ja) 1993-05-10 2002-09-05 接合安定化されたポリペプチド組成物
JP2002260459A Pending JP2003160598A (ja) 1993-05-10 2002-09-05 接合安定化されたポリペプチド組成物
JP2006202440A Expired - Lifetime JP4012928B2 (ja) 1993-05-10 2006-07-25 接合安定化されたポリペプチド組成物

Country Status (12)

Country Link
US (2) US5359030A (enrdf_load_stackoverflow)
EP (2) EP1264837A1 (enrdf_load_stackoverflow)
JP (4) JPH08510255A (enrdf_load_stackoverflow)
AT (1) ATE301134T1 (enrdf_load_stackoverflow)
AU (1) AU694919B2 (enrdf_load_stackoverflow)
CA (1) CA2162366C (enrdf_load_stackoverflow)
DE (1) DE69434448T2 (enrdf_load_stackoverflow)
DK (1) DK0707596T3 (enrdf_load_stackoverflow)
ES (1) ES2247586T3 (enrdf_load_stackoverflow)
HK (1) HK1049488A1 (enrdf_load_stackoverflow)
IL (1) IL109619A (enrdf_load_stackoverflow)
WO (1) WO1994026778A1 (enrdf_load_stackoverflow)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001048052A1 (fr) 1999-12-24 2001-07-05 Kyowa Hakko Kogyo Co., Ltd. Glycols de polyalkylene ramifies
JP2003502364A (ja) * 1999-06-19 2003-01-21 ノベックス・コーポレイション 加水分解型親油性成分を有する両親媒性薬物−オリゴマー結合体およびその製造法および使用法
JP2003206236A (ja) * 1993-05-10 2003-07-22 Nobex Corp 接合安定化されたポリペプチド組成物
JP4758608B2 (ja) * 2001-11-07 2011-08-31 ネクター セラピューティックス 分枝ポリマーおよびそれらの結合体
JP2015514108A (ja) * 2012-04-05 2015-05-18 マサチューセッツ インスティテュート オブ テクノロジー 免疫刺激組成物およびその使用方法

Families Citing this family (215)

* Cited by examiner, † Cited by third party
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US6090925A (en) 1993-03-09 2000-07-18 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US5981719A (en) 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US5681811A (en) * 1993-05-10 1997-10-28 Protein Delivery, Inc. Conjugation-stabilized therapeutic agent compositions, delivery and diagnostic formulations comprising same, and method of making and using the same
KR100361933B1 (ko) 1993-09-08 2003-02-14 라 졸라 파마슈티칼 컴파니 화학적으로정의된비중합성결합가플랫폼분자및그것의콘주게이트
DE4437502A1 (de) * 1993-12-02 1995-06-08 Basf Ag Hirudin-Konjugate aus Hirudin und lipophilen Verbindungen
US5567592A (en) * 1994-02-02 1996-10-22 Regents Of The University Of California Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal
RU2066551C1 (ru) * 1994-03-23 1996-09-20 Институт нефтехимического синтеза РАН Способ получения инсулинсодержащих полимерных гидрогелей
DE69533987T2 (de) * 1994-05-20 2006-03-16 Hisamitsu Pharmaceutical Co., Inc., Tosu Protein oder polypeptid, verfahren zur seiner herstellung und entsprechende zwischenprodukte
US5932462A (en) 1995-01-10 1999-08-03 Shearwater Polymers, Inc. Multiarmed, monofunctional, polymer for coupling to molecules and surfaces
US5869602A (en) * 1995-03-17 1999-02-09 Novo Nordisk A/S Peptide derivatives
US6251856B1 (en) 1995-03-17 2001-06-26 Novo Nordisk A/S Insulin derivatives
US6004583A (en) * 1995-03-22 1999-12-21 Orex Pharmaceutical Development Corp. Protein-containing polymer composition for oral administration
CA2190304A1 (en) * 1995-12-15 1997-06-16 Elazar Rabbani Property effecting and/or property exhibiting compositions for therapeutic and diagnostic uses
TW517067B (en) * 1996-05-31 2003-01-11 Hoffmann La Roche Interferon conjugates
ES2219773T3 (es) * 1996-08-02 2004-12-01 Orex Pharmaceutical Development Corp. Composicion polimera para la administracion de peptidos y proteinas por via oral.
US6503881B2 (en) * 1996-08-21 2003-01-07 Micrologix Biotech Inc. Compositions and methods for treating infections using cationic peptides alone or in combination with antibiotics
US6180604B1 (en) * 1996-08-21 2001-01-30 Micrologix Biotech Inc. Compositions and methods for treating infections using analogues of indolicidin
AU4981897A (en) * 1996-10-15 1998-05-11 Navix, Inc. Stabilized conjugates of uncomplexed subunits of multimeric proteins
US6132712A (en) * 1996-12-11 2000-10-17 A. Glenn Braswell Superoxide dismutase stabilized with fragments of casein and pharmaceutical compositions incorporating same
US6416778B1 (en) 1997-01-24 2002-07-09 Femmepharma Pharmaceutical preparations and methods for their regional administration
US5993856A (en) * 1997-01-24 1999-11-30 Femmepharma Pharmaceutical preparations and methods for their administration
US5804183A (en) * 1997-01-31 1998-09-08 Enzon, Inc. Arginine deminase derived from mycoplasma arthritidis and polymer conjugates containing the same
US20040009166A1 (en) * 1997-04-30 2004-01-15 Filpula David R. Single chain antigen-binding polypeptides for polymer conjugation
JP2002505574A (ja) 1997-04-30 2002-02-19 エンゾン,インコーポレイテッド ポリアルキレンオキシド修飾された単鎖ポリペプチド
RO121474B1 (ro) * 1997-06-06 2007-06-29 Kyowa Hakko Kogyo Co., Ltd. Polipeptide modificate chimic
IS4518A (is) * 1997-07-09 1999-01-10 Lyfjathroun Hf, The Icelandic Bio Pharmaceutical Group Nýtt lyfjaform fyrir bóluefni
US6165458A (en) * 1997-12-26 2000-12-26 Pharmaderm Laboratories Ltd. Composition and method for dermal and transdermal administration of a cytokine
JP2002506792A (ja) * 1998-02-27 2002-03-05 ノボ ノルディスク アクティーゼルスカブ N末端修飾glp−1誘導体
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US6703381B1 (en) * 1998-08-14 2004-03-09 Nobex Corporation Methods for delivery therapeutic compounds across the blood-brain barrier
SK287491B6 (sk) * 1998-10-16 2010-11-08 Biogen Idec Ma Inc. Fúzne proteíny interferónu- beta-1a a ich použitie
CN1329082C (zh) 1998-10-16 2007-08-01 拜奥根Idec马萨诸塞公司 干扰素-β-1a的聚合物缀合物及其使用
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HK1042287A1 (zh) * 1999-06-08 2002-08-09 La Jolla Pharmaceutical Company 包括氨基氧基的化合价平台分子
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JP2003206236A (ja) * 1993-05-10 2003-07-22 Nobex Corp 接合安定化されたポリペプチド組成物
JP2003502364A (ja) * 1999-06-19 2003-01-21 ノベックス・コーポレイション 加水分解型親油性成分を有する両親媒性薬物−オリゴマー結合体およびその製造法および使用法
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JP4593048B2 (ja) * 1999-12-24 2010-12-08 協和発酵キリン株式会社 分岐型ポリアルキレングリコール類
JP4758608B2 (ja) * 2001-11-07 2011-08-31 ネクター セラピューティックス 分枝ポリマーおよびそれらの結合体
JP2015514108A (ja) * 2012-04-05 2015-05-18 マサチューセッツ インスティテュート オブ テクノロジー 免疫刺激組成物およびその使用方法
JP2017165739A (ja) * 2012-04-05 2017-09-21 マサチューセッツ インスティテュート オブ テクノロジー 免疫刺激組成物およびその使用方法
JP2020143165A (ja) * 2012-04-05 2020-09-10 マサチューセッツ インスティテュート オブ テクノロジー 免疫刺激組成物およびその使用方法
JP2022191408A (ja) * 2012-04-05 2022-12-27 マサチューセッツ インスティテュート オブ テクノロジー 免疫刺激組成物およびその使用方法
US12303566B2 (en) 2012-04-05 2025-05-20 Massachusetts Institute Of Technology Immunostimulatory compositions and methods of use thereof

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IL109619A (en) 2000-12-06
AU6946694A (en) 1994-12-12
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EP0707596A1 (en) 1996-04-24
WO1994026778A1 (en) 1994-11-24
EP0707596B1 (en) 2005-08-03
JP4012928B2 (ja) 2007-11-28
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JP2003206236A (ja) 2003-07-22
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DE69434448T2 (de) 2006-06-08
DK0707596T3 (da) 2005-12-12
ES2247586T3 (es) 2006-03-01
EP1264837A1 (en) 2002-12-11
DE69434448D1 (de) 2005-09-08
ATE301134T1 (de) 2005-08-15
CA2162366C (en) 2009-10-27
US5438040A (en) 1995-08-01
US5359030A (en) 1994-10-25
EP0707596A4 (en) 1997-11-12
AU694919B2 (en) 1998-08-06
IL109619A0 (en) 1994-08-26

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